The integrity of the cartilage surface and its surrounding synovium affects the homeostasis and long-term function of an articulating joint. The loss of superficial zone chondrocytes and fibrillation of the cartilage surface are early signs of osteoarthritis. Intimal cell hyperplasia and sub-intimal fibrosis is striking in rheumatoid arthritis where joint destruction is, in part, mediated by aggressive and invasive synovial overgrowth. This application proposes to explore the role of the secreted protein lubricin (also known as megakaryocyte stimulating factor precursor, superficial zone protein, camptodactyly-arthropathy-coxa vara-pericarditis syndrome protein, and proteoglycan 4) in the maintenance of articulating joints. This protein has several important roles in joint homeostasis, including the protection and boundary lubrication of articulating surfaces, and the regulation of intimal cell growth. Genetic deficiency of this protein causes the autosomal recessive CACP syndrome, which is associated with precocious joint failure, and acquired deficiency of this protein likely contributes to joint failure in osteoarthritis and rheumatoid arthritis. Since lubricin is a protein that is synthesized by surface chondrocytes and synviocytes and is secreted into the synovial fluid, we speculate that it may be a useful agent, or target, in the treatment of common joint disease. This application has four major aims: Aim 1) Characterize the lubricin knockout mouse with respect to cell biological properties of synoviocytes, and the biophysical and structural properties of the articular surface (lamina splendens). Aim 2) Delineate which domains in lubricin are important for its post-translational modification and biologic properties, such as protein-protein interactions, lubrication, and cell growth regulation. Aim 3) Create a transgenic mouse in which lubricin expression can be exogenously regulated. This will allow us to explore the temporal role of lubricin in joint development and homeostasis. Aim 4) Identify hereditary and acquired alterations of lubricin function within synovial fluid from patients with CACP syndrome and common diseases of joints including osteoarthritis, rheumatoid arthritis, and traumatic joint injury.